In studies on the clinical management of pain, a combination of morphine and bupivacaine is more effective than either of them alone in producing analgesia. The present study was designed to examine the effect of bupivacaine on morphine-induced antinociception as measured by the tail-flick test in the rat. To understand the basis of this interaction, the effect of bupivacaine on the binding of opioid ligands to their spinal opioid receptors in the rat also was investigated. Intrathecal administration of 5, 20, or 50 micrograms bupivacaine significantly potentiated the antinociception produced by intrathecal administration of 10 micrograms morphine. There was more than a 10-fold increase in the area under the curve (AUC0-60 min) for morphine-induced antinociception in the presence of bupivacaine. At higher doses of morphine (20 micrograms), bupivacaine was not very effective, increased AUC0-60 min for antinociception by only about 25%, and in fact significantly decreased the total duration of morphine-induced antinociception. Radioreceptor assays done with rat spinal cord membrane preparations revealed that bupivacaine (0.1-10 nM) inhibited the binding of specific ligands to mu-receptors but increased the binding to delta- and kappa-receptors. The authors conclude that the facilitation of morphine-induced antinociception by bupivacaine may be associated with a conformational change in the spinal opioid receptors induced by bupivacaine. Although increasing the binding of morphine to kappa-opioid receptors is the most prominent effect, the binding of opioid ligands to all spinal receptors is inhibited at high doses of bupivacaine.